The Effects of Essential Oils on the Nervous System: A Scoping Review

Essential oils are a mixture of natural aromatic volatile oils extracted from plants. The use of essential oils is ancient, and has prevailed in different cultures around the world, such as those of the Egyptians, Greeks, Persians, and Chinese. Today, essential oils are used in traditional and complimentary medicines, aromatherapy, massage therapies, cosmetics, perfumes and food industries. The screening effect of essential oils has been studied worldwide. They demonstrate a range of biological activities, such as antiparasitic, antifungal, antibacterial, antiviral, antioxidant, anti-inflammatory, anticancer, antiaging, and neuroprotective properties. In this scoping review, we provide a 10-year updated comprehensive assessment of volatile oils and their effects on the nervous system. MEDLINE, Scopus, and Google Scholar were systematically and strategically searched for original studies investigating these effects from 2012 to 2022. Approximately seventy studies were selected as included studies. Among these studies, several outcomes were reported, including antistress, antianxiety, analgesic, cognitive, and autonomic effects. Some essential oils showed developmental benefits, with the potential to induce neurite outgrowth. The neurotransmitter receptor level can also be modified by essential oil application. Physiological and pathophysiological outcome measures were reported. For physiological outcomes, arousal, cognitive performance, circadian eating behavior, emotional modulation, consumer acceptance, preferences, and willingness to buy were investigated. For pathophysiological conditions, pain, depression, anxiety, stress, sleep disorder, mental fatigue, agitated behavior, and quality of life were measured. In conclusion, essential oils showed promising effects on the nervous system, which can be further applied to their use in functional foods, drinks, and alternative therapy.


Introduction
Essential oils (EOs) are the naturally aromatic oily liquids produced by plants, which are responsible for their essence or odor. EOs are found in great quantities in plant oil sacs or oil glands. EOs can be extracted from different parts of plants, including their leaves, barks, flowers, buds, seeds, and peels. As EOs are a concentrated hydrophobic mixture of hydrocarbon volatile compounds that easily evaporate at room temperatures, they are also known as volatile oils. Thus, inhalation via the olfactory system is a common method of use. During the extraction, most volatiles oil are commonly and easily isolated through steam-or hydro-distillation methods. However, for the oils produced from the rind of fruits such as those in the citrus family, the cold-pressed or expressed oils extraction method is usually used. A solvent extraction method is also used for some plant materials that cannot tolerate heat (in steam) or be subjected to cold-pressing, such as the rose, neroli, tuberose, jasmine, and oak [1]. In most plants, the major components of EOs are terpenoid and phenylpropanoid derivatives. Terpenoids are the main components (comprising approximately 80%), but phenylpropanoid provides the flavor and odor of the EOs. Terpenoid and phenylpropanoid are derived from different primary metabolic precursors by different biosynthetic pathways. The pathways for terpenoids synthesis are mevalonate and mevalonate independent (deoxyxylulose phosphate), whereas phenylpropanoids synthesis occurs through the shikimate pathway [2,3]. The scent and bioactivity of EOs depends on their chemical compositions. Different EOs from different plant species and habitats have various potentials. According to the various biological properties, EOs have been widely used and have attracted increased attention in recent years. The primary use of EOs started in the medical field. The term "essential oil" comes from "quinta essentia" in ancient Latin, which means the fifth element. The fifth element is the spirit or life force integrated with the other four elements: fire, air, earth, and water. The isolation of essential oil was thought to be the process of removing the spirit from the plant and the oils were used as healing essences with medical benefits [3]. Until now, the use of EOs has been studied and demonstrated across a range of biological activities, exhibiting antiseptic, antibiotic, antifungal, antiviral, anti-inflammatory, antioxidants, anti-cancer, antinociceptive, carminative, laxative, rubefacient, antidepressant, anticonvulsant, analgesic, sedative, and immunomodulatory properties [4]. EOs have been widely applied in plants and animals industries, perfumery, cosmetics, food, and pharmaceuticals. The popularity of EOs and aromatic plants is also continuously growing according to their various activities and the increase in consumer demand. The use of EOs for the human body or routes of administration occurs not only via inhalation, but also including skin absorption (topical or aromatherapy), as well as ingestion. However, inhalation via the olfactory system is the fastest and easiest method. It has been reported that EOs affect the immediate changes in the autonomic nervous system and physiological responses such as pupil dilation, blood pressure, muscle tone, pulse rate, skin temperature, and brain activity. These body responses improve physical, mental, and emotional well-being after 15 min of inhalation [5][6][7]. The component of EOs is detected by the olfactory receptors on a nasal olfactory epithelium, which causes the stimulation of olfactory nerves and transmission of a signal to the central nervous system, including the limbic system and hypothalamus, which further modulate human behavior and body function [7]. These indicate that the nervous system is the very first mechanism of the body's response to EOs. There has been a lot of research in this growing field of study. However, there is no updated summary or review describing the physiological and pathophysiological outcomes of the nervous system. There are a limited number of systematic review articles in the database providing more specific topics such as the pharmacological properties of EOs or confined health outcomes. The systematic scoping review will show more broad outcomes from basic physiology to more sophisticated pathophysiology in animal and human research. Therefore, we updated and discussed the 10-year evidence related to EOs in relation to the physiological and pathophysiological outcomes of the nervous system in a systematic scoping review.

Essential Oils and Application Methods
According to the included studies, the effects of essential oils on the nervous system have been widely studied in every region around the world. Several types of essential oils were used in the included studies. In this scoping review, we included both animal and human studies to comprehensively understand the possible mechanisms to outcome measures in humans. The PubMed database showed more specific results than others; however, Scopus and Google Scholar showed more sensitivity than PubMed (Figure 1). Based on the PubMed database, 81.43% of the included studies were conducted on humans, 18.57% were carried out on animals and about 1.43% were researched on cell cultures. Lavender essential oil was the most used essential oil, appearing in approximately 30.71% of the studies. The second most popular category of essential oil in the studies is the Citrus spp., which includes essential oils such as orange, bergamot, grapefruit, and lemon (24.4%). Rosemary essential oil was the third choice after the lavender oil and Citrus spp. oil (5.51%). Mint, rose, cedar wood, geranium, lemon grass, chamomile, cinnamon, and others were also used, though in smaller amounts. The routes of administration used in the included studies including inhaled, oral, topical, massage, injection, and immersion. Inhalation was the most popular route of administration at approximately 58.57%. There was a wide range of study populations and age groups, as reported in Table 1.
Molecules 2023, 28, x FOR PEER REVIEW 3 of 24 humans, 18.57% were carried out on animals and about 1.43% were researched on cell cultures. Lavender essential oil was the most used essential oil, appearing in approximately 30.71% of the studies. The second most popular category of essential oil in the studies is the Citrus spp., which includes essential oils such as orange, bergamot, grapefruit, and lemon (24.4%). Rosemary essential oil was the third choice after the lavender oil and Citrus spp. oil (5.51%). Mint, rose, cedar wood, geranium, lemon grass, chamomile, cinnamon, and others were also used, though in smaller amounts. The routes of administration used in the included studies including inhaled, oral, topical, massage, injection, and immersion. Inhalation was the most popular route of administration at approximately 58.57%. There was a wide range of study populations and age groups, as reported in Table  1.

Physiological Outcomes
Several levels of physiological hierarchy were investigated (Table 2). At the very first level of alertness, electroencephalography was used to evaluate the arousal and sedative properties in animals and humans. Lavender oil showed a sedative effect. Peppermint and coffee showed a stimulating effect, as shown by the electroencephalogram. The autonomic nervous system was frequently measured after the alertness level. Heart rate (HR), blood pressure (BP), respiratory rate (RR), and heart rate variability (HRV) were evaluated. Lavender, rosemary, bergamot, eucalyptus, rose, yuzu, lemon, Meniki, Hinoki, Juniperus phoenicea gum extract, Copaifera officinalis (Balsam Copaiba) resin, Aniba rosaeodora (Rosewood) wood oil, Juniperus virginiana oil, grapefruit oil, and petitgrain revealed autonomic nervous system (ANS) activity modification via the inhalation route. A massage with lavender and geranium oils also affected the ANS by reducing heart rate and blood pressure after the massage. In the opposite of alertness, lavender improved objective sleep quality. For another type of alertness and arousal, peppermint, rosemary, grapefruit, and cinnamon

Physiological Outcomes
Several levels of physiological hierarchy were investigated (Table 2). At the very first level of alertness, electroencephalography was used to evaluate the arousal and sedative properties in animals and humans. Lavender oil showed a sedative effect. Peppermint and coffee showed a stimulating effect, as shown by the electroencephalogram. The autonomic nervous system was frequently measured after the alertness level. Heart rate (HR), blood pressure (BP), respiratory rate (RR), and heart rate variability (HRV) were evaluated. Lavender, rosemary, bergamot, eucalyptus, rose, yuzu, lemon, Meniki, Hinoki, Juniperus phoenicea gum extract, Copaifera officinalis (Balsam Copaiba) resin, Aniba rosaeodora (Rosewood) wood oil, Juniperus virginiana oil, grapefruit oil, and petitgrain revealed autonomic nervous system (ANS) activity modification via the inhalation route. A massage with lavender and geranium oils also affected the ANS by reducing heart rate and blood pressure after the massage. In the opposite of alertness, lavender improved objective sleep quality. For another type of alertness and arousal, peppermint, rosemary, grapefruit, and cinnamon oils improved vigilance using a vigilance test. In response to olfactory stimuli, the cortisol level and salivary chromogranin A were affected by lavender, bergamot, yuzu, Juniperus phoenicea gum extract, Copaifera officinalis resin, Aniba rosaeodora wood oil, Juniperus virginiana oil, and grapefruit essential oil.
In addition to the objective measure of stress hormones, these oils also affected subjective emotional measurements. Interestingly, most essential oil use decreased stress and negative emotions with the reduction in stress hormones and parasympathetic stimulation. Anxiolytic effects were reported in lavender, Juniperus phoenicea gum extract, Copaifera officinalis resin, Aniba rosaeodora wood oil, Juniperus virginiana oil, Origanum majorana, Citrus sinensis, and petitgrain. At the uppermost levels, cognitive functions and behaviors were finally affected by essential oils. Rosemary essential oil improved cognition using a computerized cognitive task. Spearmint and peppermint essential oils modulated performance during a demanding cognitive task and reduced mental fatigue during a prolonged cognitive task. Petitgrain essential oil could improve performance in the workplace when added to an aroma diffuser in the work room. Oregano and rosemary essential oils increased consumer acceptability and willingness to buy food products. Among the positive results, there were also negative results. Lavender could not modulate stress and ANS responses in patients with coronary bypass surgery, which only affected systolic blood pressure. Koteless and Babulka also showed negative effects of rosemary, lavender, and eucalyptus oils on adult volunteers.

Pathophysiological Outcomes
Depression was the most studied clinical manifestation related to the effect of essential oils. Lavender, chamomile, bergamot, sweet orange, anise, geranium, and mountain pepper reduced depression in the elderly, postpartum women, restless patients, breast cancer patients, irritable bowel syndrome patients, mixed anxiety and depressive disorder, and residents in a long-term care unit. Analgesic and anxiolytic effects were the second most attractive topics. Lavender, bergamot, and Melissa officinalis (lemon balm) showed an analgesic effect, which can be observed in mice, rats, neonatal, premature babies, and women with dysmenorrhea. Lavender, bergamot, geranium, mountain pepper, chamomile, Juniperus phoenicea gum extract, Copaifera officinalis resin, Aniba rosaeodora wood oil, Juniperus virginiana oil, and Citrus spp. oil showed anxiolytic activity in several types of populations. Other interesting outcomes in different groups of patients were reported as described in Table 3. Essential oils could alleviate fatigue, memory problems, behavioral symptoms, stress, inhalant cravings, and sleep problems without the potential for abuse. They still showed negative effects on several groups of breast cancer patients undergoing breast reconstruction, children with burns, mild to moderate dementia sufferers older than 65 years old, and coronary bypass surgery patients.

Mechanism Studies from Basic Research
Lavender was one of the essential oils that was completely researched in terms of its safety and mechanisms in humans (Table 4). From the imaging study, it was found that Silexan intake, a patented product of lavender oil, showed a reduction in serotonin-1A receptor binding in several brain areas. Acori Tatarinowii Rhizoma showed a synergistic effect with the nerve growth factor in pheochromocytoma PC12 cells potentiating neurite outgrowth in an essential oil co-treatment group. Menthol could increase the circadian eating behavior in animal research. The treatment of alpha (α)-and beta (β)-pinene could reduce the nitrite level in the hippocampus and lower dopamine and norepinephrine levels in the striatum, resulting in seizure intensity reduction. Ocimum gratissimum essential oil showed anesthetic properties and reduced stress in Nile tilapia during transport. Coriander oil and linalool showed a sedative effect, reducing stress-related behaviors in chicks in a manner similar to the effects of diazepam. Lavender, peppermint, rosemary, grapefruit, bergamot, and yuzu could modulate autonomic nervous system function, resulting in changes in cardiovascular parameters and cortisol release. Citronellol showed a nociceptive effect of orofacial pain via the retrosplenial cortex and periaqueductal gray activations. Bergamot oil also reduced the central sensitization-phase-related pain and agitation behaviors in a mouse model. Peppermint essential oil reduced mental fatigue and prolonged cognitive tasks with acetylcholinesterase inhibitory and gamma-aminobutyric acid A receptor stimulating properties. Geraniol oil also improved learning and memory impairment related to aging.  Table 2. Effects of essential oils on physiological responses.

Author Essential Oils Application Methods Measures Outcomes
Du et al. [13] lemon and grapeseed inhaled cognitive function tests shortened reaction time response, more impulsive decision-making Dehghan et al. [14] lavender, rosemary, and orange inhaled retrospective and prospective memory scale only lavender or rosemary can reduce some memory problems in hemodialysis patients by reduction of retrospective memory problems Brnawi et al. [46] cinnamon bark and leaf oral a 9-point hedonic scale natural antimicrobial ingredient in milk beverages-sensory aspect

Discussion
In this scoping review, we updated the effects of essential oils on the nervous system for this decade in terms of physiological and pathophysiological conditions. The number of studies on essential oils is increasing year by year, and more mechanisms are being revealed. The PubMed search strategy showed more specific research compared with Scopus and Google Scholar. However, a number of studies were found in the Scopus and Google Scholar databases. In this review, we intended to provide a comprehensive view of this issue. Therefore, we included both animal and human research to completely explain the beneficial properties and related mechanisms. We did not perform risk of bias in this systematic scoping review. Most of the excluded studies were not related to nervous system function and were written in other languages. The population covered in this review is broad, as reported in Table 1, to show the previous use of essential oils in many possible models. We analyzed the included studies and categorized the physiological and pathophysiological modifications.
It is not only the olfactory system that plays a role in this intervention; the direct effect of odorant compounds also takes part in the central nervous system [77]. The intervention mechanisms might be split into two forms: action via the olfactory system and action via the oil's own chemical properties. Actions in both physiology and pathophysiology ranges through the olfactory system connect with the hypothalamus, limbic system, and prefrontal cortex, exerting body responses [61]. The suprachiasmatic nucleus (SCN) plays an important part in our sense of smell [78]. In the hypothalamus-hypophysis-adrenal axis, essential oils and emotional signals from the prefrontal cortex, amygdala, and hippocampus could reduce corticotropin-releasing hormone (CRH), which then reduced the adrenocorticotropic hormone (ACTH). The reduction in ACTH leads to a lower release of stress hormone as cortisol in serum [30,53,58]. Autonomic nervous system activity from odorants is also involved with SCN, which in turn reduces sympathetic activity and increases parasympathetic activity. Endogenous opioids are an important factor in mental issues [79]. These activities were observed using cardiovascular parameters and the responses of other organs such as the pupils, skin, and gastrointestinal system, or based on cerebral activity [80]. In the physiological range, most of the essential oils used in research cause body responses in a parasympathetic fashion. Interestingly, menthol can cause a cold perception triggered by transient receptor potential channel (TRP) stimulation. This psychological perception of TRP could increase the sympathetic response and food intake [81]. Another psychological aspect is distraction, and aromatherapy also successfully distracted patients or participants from anxiety, stress, and pain [31]. Regarding the chemical properties of essential oils, many receptors of neurotransmitters are involved, such as gamma-aminobutyric acid (GABA) A receptor, n-methyl-D-aspartate (NMDA) receptor, serotonin (5-HT) 1A receptor, and a voltage-dependent calcium channel. For arousal, GABA and NMDA receptors take part in the function causing sedative or stimulating effects. Linalool increased the chloride current from GABA receptor stimulation, which then caused sedation. For depressive symptoms, 5-HT is the ideal neurotransmitter system used in antidepressants. Silexan showed a reduction in 5-HT1A receptor binding after oral route administration for 8 weeks [68]. This action might be the mechanism of anxiolytic and antidepressant activities. Essential oils still have a direct effect on the nociceptor in case of analgesic effect [82].
Regarding the null results in children with burns, breast reconstruction patients, and open-heart surgery patients, there are several explanations in these cases [18,39,50]. Very young children showed a low level of stress compared with adults or older children because they could comfort themselves by being close to their parents. Intense distress can happen as a result of cancer diagnoses and surgery causing concerns about a lower household income, reduced social support, and higher tumor stage. There is a strong level of fear associated with acute procedures involving invasive interventions such as open-heart surgery. This scoping review showed broad, complex health outcomes from basic mechanisms to pathophysiology through a key strategic search. There is a limitation related to the outcome measures related to explicit measures based on rating methodology. Objective measures were used for most of the physiological parameters. To compare efficacy among EOs, the dose of EOs, duration of application, risk of bias, and measures need to be comparable. The objective or implicit measures will provide a benefit when comparing efficacy. Altogether, essential oils showed beneficial effects on the nervous system in both physiological and pathological ranges. Concern about pathologic mechanisms and actions of essential oils in terms of types, as well as the administration route, will benefit wellbeing and quality of life.

Question
Preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews were used as guidelines during the preparation of this scoping review. The scoping review intended to update the comprehensive evidence to answer the following question: "What are the effects of essential oils on the nervous system?"

Search Strategy
To completely answer the question, we set up a strategic search concerning sensitivity and specificity to identify literature related to the nervous system. Three electronic databases-PubMed, Scopus, and Google Scholar-were used in this study, which was conducted by two independent reviewers (AS and PK) on 5 October 2022. A search strategy for PubMed was created using a combination of MeSH terms and Boolean operators "AND", "

Study Selection
Duplicated studies were filtered using Endnote. Two reviewers (AS and PK) independently screened the titles and abstracts of all studies and subjected them to the inclusion and exclusion criteria. For the inclusion criteria, original articles written in English and describing animal and human studies were selected for every age group and health condition. For the exclusion criteria, articles published in other languages and including no outcome of the nervous system were excluded. Then, the full texts were downloaded and evaluated. Any disagreements during the selection processes were resolved via discussion and consensus between the two writing reviewers.

Data Charting Process
The data extraction process was performed by two writing reviewers (AS and PK). A standardized data extraction form including the author, year, study design, type of essential oils, route of administration, population, outcome measure methodology, and outcome was extracted using Microsoft Excel software. Any disagreements during the selection processes were resolved via discussion and consensus between the two writing reviewers. Tables listing the essential oils and outcomes were created to conclude the selected studies.

Conclusions
Essential oils showed beneficial effects on the nervous system in both animal and human research via the olfactory system and its chemical properties, impacting physiology and pathophysiology.